Adverse Outcome Pathway on chronic binding of antagonist to N-methyl-D-aspartate receptors during brain development leading to neurodegeneration with impairment in learning and memory in aging

This AOP links chronic NMDA receptors inhibition during brain development to neurodegeneration in hippocampus and cortex with amyloid plaque deposition and tau hyperphosphorylation, and impairment of learning and memory, which are considered as hallmark of Alzheimer's disease. It makes use of some KEs and KERs from AOP 13 and introduces Neuroinflammation as KE, which is involved in several neurodegenerative diseases. This AOP is based on the hypothesis of Landrigan and coworkers (2005) proposing an early origin of neurodegenerative diseases in later life. The chemical initiator used in this AOP for the empirical support is lead (Pb). In adults, cumulative lifetime Pb exposure is also associated with decline in cognition, suggesting that long-term exposure during development or occupational exposure increases the risk to develop neurodegenerative disease. The long latency period between exposure and late-onset of effects gives a very broad life-stage applicability. The gap of knowledge is mainly due to limited quantitative evaluations.